Certain N-phenyl or N-pyridyl aza sulfonium salts

ABSTRACT

Preparing indoles and intermediates therefor by reacting an N-haloaniline with a β-carbonylic hydrocarbon sulfide to form an azasulfonium halide, reacting the azasulfonium halide with a strong base to form a thio-ether indole derivative, and then reducing the thio-ether indole, e.g. with Raney nickel, to form the indole compound. When an acetal or ketal of the β-carbonyl hydrocarbon sulfide is used, the azasulfonium salt is treated with a base, and then with an acid to form the thio-ether indole derivative. When an α-ethyl-β-carbonylic hydrocarbon sulfide is used, the resulting azosulfonium salt reacts with strong base to form a thio-ether indolenine derivative, which on reduction with Raney nickel or complex metal hydrides yields 3-substituted indoles. The aniline may be an aminopyridine to form an aza-indole compound in the process. The azasulfonium salts and thio-ether indole or thio-ether indolenine derivatives can be isolated and recovered from their respective reaction mixtures. The thio-ether-indole and thio-ether indolenine derivatives are useful as intermediates to make the indoles without the thio-ether group. The indoles are known compounds having a wide variety of uses, e.g., in making perfumes, dyes, amino acids, pharmaceuticals, agricultural chemicals and the like.

The invention described herein was made in the course of work under agrant or award from the Department of Health, Education and Welfare.

This application is a division of application Ser. No. 573,069, filedApr. 30, 1975, now U.S. Pat. No. 3,992,392 issued Nov. 16, 1976 which isin turn a division of application Ser. No. 355,198, filed Apr. 27, 1973,now issued U.S. Pat. No. 3,901,899, issued Aug. 26, 1975.

FIELD OF THE INVENTION

This invention relates to processes for making indoles. Moreparticularly, this invention provides an improved process for preparingvarious substituted and unsubstituted indoles and intermediatestherefor.

The Fischer indole synthesis [E. Fischer and F. Jourdan, Chem. Ber., 16,2241 (1883); E. Fischer and O. Hess, ibid., 17, 559 (1884); E. Fischer,Justus Liebigs, An. Chem., 236, 126 (1886)., and B. Robinson, Chem.Rev., 69, 227 (1969)] has received the most widespread use because it,coupled with the Japp-Klingemann reaction [Chem. Ber., 20, 2942, 3284,3398 (1887); Orq. Reactions, 10, 143, (1959)] has been the mostversatile and widely applicable method of obtaining indoles up to thistime. However, because of some inherent disadvantages to that processthere is a need in the art for a more efficient, more economical processfor making indole, indole intermediates, and indole derivatives.

Other prior art that might be considered pertinent is the following: a)P. Claus and W. Vycudilak, Monatsh. Chem., 101, 396 (1970), whereinClaus et al reacted an aniline with a dimethylsulfoxide to form asulfiliminic acid, not an azasulfonium salt; and b) P. Claus, W.Vycudilik, and W. Rieder, Monatsh. Chem., 102, 1571 (1971), whereinthese sulfiliminic compounds are thermally rearranged tohydrocarbon-S-hydrocarbon aromatic amine thio-ethers. Other papers whichcan be considered include our own publication in Tetrahedron Letters,No. 6, pp. 497-500 (1972) and that of Prof. C. R. Johnson et. al.,Tetrahedron Letters, No. 6, pp. 501-504 (1972). In addition, the paperof U. Lerch and J. G. Moffatt entitled "Carbodiimide-SulfoxideReactions. XIII. Reactions of Amines and Hydrazine Derivatives" in theJournal of Organic Chemistry, Vol. 36, 3861 (1971) may be considered aspertinent as the Claus publications, supra. See also "The Chemistry ofIndoles" by R. J. Sundberg, Academic Press, New York (1970) and"Indoles" Part I, by R. K. Brown, W. J. Houlihan Ed., WileyInterscience, New York, (1972). Also, pertinent is our publication in J.Amer. Chem. Soc., 95, 590, 591 (1973).

SUMMARY OF THE INVENTION

Briefly, I have discovered that indoles can be prepared by reacting anN-haloanline with a β-carbonyl hydrocarbon-S-hydrocarbon sulfide, or anacetal or ketal form thereof, under mild, substantially anhydrousconditions to form an azasulfonium halide salt, which can be isolated,is desired, and thereafter treating the azasulfonium salt with a base toform a thio-ether substituted indole or thio-ether substitutedindolenine compound if a β-carbonyl sulfide or α-alkyl-β-carbonylsulfide had been used, respectively, or with a base and then with acidif a β-carbonyl sulfide acetal or ketal had been used, to form thethio-ether substituted indole or thio-ether substituted indolenine.Thereafter, if desired, the thio-ether indole or thio-ether indoleninecan be reduced, e.g., with Raney nickel, to remove the thio-ether groupfrom the indole. This process is applicable to both anilinesandaminopyridines. This process can be conducted through its severalsteps in one reaction vessel, without separation of the intermediatereaction products up to the isolation of the thio-ethers. However, insome cases it may be preferred for yield economies to isolate and atleast partially purify the azasulfonium salt and thio-etherintermediates before continuing the process.

OBJECTS OF THE INVENTION

It is an object of this invention to provide an improved process formaking indoles using primary and secondary aromatic amines andβ-carbonyl sulfides or acetal or ketal forms of the β-carbonyl sulfidesas reactants in the process

It is another object of this invention to provide a process for makingindoles and intermediates therefor which enables a less tedioussynthesis and the use of more readily available, less expensive reactantchemicals under milder reaction conditions, which now permits the use ofaniline starting materials containing substituents which otherwise couldnot be used.

Other objects, aspects and advantages of the invention will be apparentto the person skilled in this art from the specification and claimswhich follow.

DETAILED DESCRIPTION OF THE INVENTION

More specifically, this invention provides an improved process formaking azasulfonium salt intermediates which are useful for makingindoles which are known and which have a wide variety of known uses.

According to the process of this invention, a primary or secondaryaniline or amino-pyridine starting material, both being referred tohereinafter as an aniline, is first reacted with a source of positivehalogen to prepare the N-haloaniline. Many sources of positive halogenare known and can be used to form the N-haloanilines. Examples ofpositive halogen sources for this reaction include tertbutylhypochlorite, N-chloro-succinimide, calcium hypochlorite, sodiumhypochlorite, sodium hypobromite, and the like. The N-chloro anilinesare preferred for reasons of availability of reactants to make them andcost of materials, but other positive halogen compounds can be used tomake useful N-haloanilines for use in this process.

The essential features of the process comprise: (a) reacting undersubstantially anhydrous conditions in an organic diluent, at atemperature ranging from the Dry-Ice/acetone mixture temperatures(about-78° C) to about 20° C an N-halo-aniline of the formula ##STR1##wherein R is hydrogen or a hydrocarbon radical free from aliphaticunsaturation containing from 1 to 8 carbon atoms:

A denotes chlorine or bromine, but is preferably chlorine:

X is --CH═ or --N═ is in a position ortho, meta or para relative to the--N(R)A group;

each of Y and Z is hydrogen or is a substituent which does not donateelectrons more strongly than m-methoxy, m-hydroxy, or a p-acetoxy group,and not more than one of Y and Z, as a substituent, is ortho to the--N(R)A group position on the ring;

the --N(R)A group position on the ring having at least one ring carbonatom ortho thereto in an unsubstituted state;

with a β-carbonyl sulfide compound or a β-carbonyl sulfide acetal orketal compound having a formula selected from the group consisting of##STR2## wherein R¹ is lower alkyl, or phenyl;

R² is hydrogen, lower alkyl, or phenyl;

R³ is hydrogen, lower alkyl, phenyl or benzyl;

R² can be attached to R³ as part of a cyclic ring system containing 5 to8 carbon atoms,

each R⁴ is lower alkyl or the two R⁴ radicals are taken together withthe ##STR3## moiety to complete a cyclic ketal or acetal having from 3to 4 carbon atoms in the ring, for a time sufficient to form anazasulfonium salt having a formula selected from the group consisting of##STR4## wherein X, Y, Z, R, R¹, R², R³, each R⁴ and A are as definedabove;

b. reacting the azasulfonium salt (IV) (R³ ═ H) with a substantiallyanhydrous base, that is, one whose conjugate acid has a pKa greater thanabout 6, to effect rearrangement of the azasulfonium salt and to form athio-ether compound of the formula ##STR5## wherein X, Y, Z, R, R¹, andR² are as defined above, and wherein the perforated hexagon containingX, Y and Z denotes a fused benzo (phenyl) or pyridyl ring in which X isin the 4-, 5-, 6- or 7-position relative to the indole ring nitrogen,when the azasulfonium salt had formula IV, that is, when theazasulfonium salt was derived from the free β-carbonyl sulfide reactantII (R³ ═ H); or reacting the azasulfonium salt of formula V (R³ ═ H)with substantially anhydrous base to form a compound of the formula VII##STR6## wherein the --C(R³)(SR¹ )[-C(OR⁴)₂ R² ] radical is ortho to the--N(R)H position on the ring;

c. if compound VII is formed in step (b), treating the compound VII withacid, preferably an economical mineral acid such as aqueous hydrochloricacid, sulfuric acid, phosphoric acid, or the like, sufficient in amountand strength to effect hydrolysis of the OR⁴ ketal (or acetal) groupsand to form a compound of the formula VI, above;

d. reacting the azasulfonium salt (IV) (R³ = alkyl and R is hydrogen, orR³ and R² connected to form a ring and R is hydrogen) with asubstantially anhydrous base, that is, one whose conjugate acid has apKa greater than about 6, to effect rearrangement of the azasulfoniumsalt and to form a thio-ether compound of the formula ##STR7## when X,Y, Z, R¹, R², and R³ are defined above, and wherein the perforatedhexagon containing X, Y, and Z denotes a fused benzo (phenyl) or pyridylring in which X is in the 4-, 5-, 6-, or 7-position relative to theindole ring nitrogen, when the azasulfonium salt had formula IV, thatis, when the azasulfonium salt was derived from the free β-carbonylsulfide reactant II (R═ H, R³ = alkyl, phenyl or benzyl or R³ connectedto R² in a ring); or reacting the azasulfonium salt of formula V (R═ H,R³ =alkyl, phenyl or benzyl or R³ connected to R² in a ring) withsubstantially anhydrous base to form a compound of the formula VIIwherein the --C(R³)(SR¹)[-C(OR⁴)₂ R₂ ] radical is ortho to the --NH₂position on the ring;

(e) if compound VII (R═H and R³ =alkyl, phenyl or benzyl or R³ and R²connected to form a ring and R═H) is formed in step (b), treating thecompound VII with acid, preferably an economical mineral acid such asaqueous hydrochloric acid, sulfuric acid, phosphoric acid, or the like,sufficient in amount and strength to effect hydrolysis of the OR⁴ ketal(or acetal) groups and to form a compound of the formula VIII, above.(f) treating the indole derivative of formula VI from step (b) or fromstep (c), or the indolenine derivative of formula VIII from step (d) orfrom step (e) with a desulfurizing reducing agent, e.g., with Raneynickel or its equivalent, to form a compound having a formula selectedfrom the group consisting of ##STR8## from the compound of formula VI,and ##STR9## from the compound of formula VIII, wherein in eachrespective formula X, Y, Z, R, R² and R³ are as defined above, and theperforated line hexagon has the same meaning as indicated above.

As used herein the term "lower alkyl" means a C₁ to C₆ -alkyl radical,e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl, neopentyl, n-hexyl, and the like. The term "lower alkyloxy"denotes a C₁ to C₆ -alkyl-O-group wherein the C₁ to C₆ -alkyl is asexemplified above. The term "lower acyloxy" denotes formyloxy and a C₁to C₆ -alkyl-C(O)O-group wherein the C₁ to C₆ -alkyl is exemplified asabove.

The aniline and aminopyridine compounds which can be used as startingmaterials in this process are those which have a free, unsubstitutedcarbon position on the aromatic ring ortho to the amino nitrogen group.Such compounds are known or are obtainable by known procedures. Many ofthem are described in publications such as "Chem Sources", DirectoriesPublishing Co., Flemington, N.J. 08822 (1972). The aniline may beunsubstituted or may contain one or more substituents, preferably notmore than two substituents on aromatic ring carbon atoms. Thesubstituents should be atoms or groups which do not donate electronsmore strongly than say, methoxy, in the meta-position or more stronglythan acetoxy in the para or ortho position. Not more than one of suchsubstituents should be ortho to the --N(R)A group position. The --N(R)Agroup position of the anilne compound must have at least one ring carbonatom ortho thereto in the unsubstituted state. Examples of substituentswhich can be in the ring include haloen (fluorine, chlorine, bromine,iodine), nitro, cyano, N,N-di-loweralkylamino, lower alkyl, loweralkyloxy, lower acyloxy, a carbonyloxy-lower alkyl andcarbonyloxy-phenyl groups. Examples of useful starting compounds includeaniline, 3-chloroaniline, 4-chloroaniline, 3,4-dichloroaniline,3-fluoroaniline, 4-fluoroanilne, 3-bromoaniline, 4-bromoaniline,4-iodoaniline, 3-nitroaniline, 4-nitroaniline, 3-cyanoaniline,4-cyanoaniline, the toluidines such as 2-methylaniline, 3-methylaniline,4-methylaniline, 4-ethylaniline, 4-hexylaniline, 3-propylaniline,3-chloro-4-methylaniline, the lower alkyloxy-substituted anilines suchas 3-methoxyaniline, 4-acetoxyaniline, 4-propionoxyaniline,4-hexanoyloxyaniline, the 3- and 4-carbonyloxy-lower alkyylanilines suchas benzocaine (4-ethoxy-carbonylaniline), 4-methoxycarbonylaniline,3-propoxycarbonylanilne, as well as 3-phenoxycarbonylaniline,4-phenoxycarbonyl-aniline, and the aminopyridines such as2-aminopyridine, 4-methyl-2-aminopyridine, 4-ethyl-2-aminopyridine,4-hexyl-2-amino-pyridine, 4-methoxy-2-aminopyridine,4-hexyloxy-2-aminopyridine, 3-aminopyridine, 4-amino-pyridine,3-bromo-4-aminopyridine, 3-iodo-4-aminopyridine,4-ethoxycarbonyl-2aminopyridine, 4-chloro-2-aminopyridine, and the like.Secondary anilines and aminopyridines which may be used include thosehaving a C₁ to C₈ -hydrocarbon group bonded to the amino nitrogen andinclude the N-C₁ to C₈ -alkylanilines and aminopyridines such as theN-methyl, N-ethyl, N-butyl, N-tert-butyl, N-octylanilines andaminopyridines as well as the N-phenyl, N-tolyl, N-xylylanilines andaminopyridines and the N-cycloalkylanilnes and aminopyridines such asN-cyclopropyl, N-cyclobutyl, N-cyclopentyl, N-cyclohexyl andN-cyclooctylanilines and aminopyridines, and such compounds substitutedon ring carbon atoms thereof with halogen, nitro, cyano, lower alkyl,lower alkyloxy, lower acyloxy, a carbonyloxy-lower alkyl or acarbonyloxy-phenyl as exemplified above.

The β-carbonyl sulfide and β-carbonyl sulfide acetal and ketal reactantsof formulas II and III above, are exemplified by the acetonyl alkylsulfides such as acetonyl methyl sulfide, acetonyl ethyl sulfide,acetonyl isopropyl sulfide, acetonyl butyl sulfide, acetonyl hexylsulfide, and acetonyl phenyl sulfide, the alkylthioacetaldehydes such asthe methylthioacetaldehyde, ethylthioacetaldehyde,isopropylthioacetaldehyde, butylthioacetaldehyde,pentylthioacetaldehyde, hexylthioacetaldehyde, phenylthioacetaldehyde,benzylthioacetaldehyde, as well as the alkylthio-, phenylthio- andbenzylthio substituted ketones such as methylthiometyl ethyl ketone,α-ethylthioethyl ethyl ketone, α-propylthio methyl hexyl ketone,α-phenylthio butyl phenyl ketone, α-ethylthio ethyl phenyl ketone,α-methylthio-benzyl phenyl ketone, α-ethylthioethyl benzyl ketone,methyl phenacetyl sulfide, 2-methylthiocyclohexanone, 2-methylthiocyclopentanone, 2-methylthiocycloheptanone, and the like, and thedimethyl, diethyl, dipropyl, dibutyl, dipentyl dehexyl and ethylene andpropylene glycol acetal and ketal derivatives of such ketones andaldehydes. Use of the acetal or ketal form of the β-carbonyl sulfidereactant to form the azasulfonium salt results in the formation of anisolatable intermediate, having general formula VII, when theazasulfonium salt is treated with a base. Treatment of this ketal oracetal intermediate VII with an acid to hydrolyze the alkyl ketal oracetal protecting group from the oxygen results in the formation of theindole thio-ether derivative of structure VI when R³ = hydrogen, and theformation of the indolenine thioether derivative of structure VIII whenR=H and R³ = alkyl or R³ is connected to R² to form a ring. In somecases the yields of the insole thio-ether structure compound are higherby isolating the intermediate VII from its reaction mixture, and atleast partially purifying it, before treating it with acid to form theinsole thio-ether compound or the indolenine thio-ether derivative butit is not necessary to isolate intermediate VII in this process.

The reactions in this process up to the point of base addition arepreferably conducted at relatively low temperatures, say, from thecooling temperatures obtained by using Dry Ice/acetone mixtures(about-78° C) to about 20° C, more preferably below about 0° C, althoughthe reaction temperature becomes less critical after the azasulfoniumsalt is formed. When the base addition is completed the reactionmixtures need not be cooled. The reactions between the aniline and thehalogenating agent to form the N-haloanilne, the N-haloaniline and theβ-carbonyl sulfide reactant or the acetal or ketal form thereof to formthe azasulfonium salt, and between the azasulfonium salt and the baseare preferably done in an organic liquid solvent medium at a temperaturebelow 0° C. Thereafter, the temperature of the mixture can be allowed torise at room temperature. Acid, if necessary to treat the acetal orketal groups, can be added at any convenient temperature, within therange indicated above, but preferably at say, 0° C to 50° C.

The reactions of this process can be conducted in a wide variety ofinert organic solvents and diluents. Solvents as extreme in polarity astoluene and methanol can be used. Methylene chloride has been mostcommonly used, but solvents such as tetrahydrofuran, chloroform,acetonitrile and the like can also be used.

The azasulfonium halide salt and base treatment steps of the process areconducted under substantially anhydrous conditions; that is, areasonable degree of care is taken to avoid the introduction of waterinto the reaction mixture during these steps, although the introductionof small incidental amounts of water introduced with solvents orreactants is not substantially detrimental to the process.

The base which is reacted with the azasulfonium salt, IV or V, can beany base which will cause formation of an ylid intermediate, which willundergo a Sommelet-Hauser type of rearrangement, and effect hydrogentransfer to produce the insole thioether VI or the acetal or ketal VII.Bases which can be used for this purpose are those which have aconjugate acid with a pKa of greater than about 6 and include, e.g.,alkanolic alkali metal hydroxides such as methanolic sodium hydroxide,potassium hydroxide, lithium hydroxide and calcium hydroxide, as well assodium methoxide, potassium methoxide, sodium and potassium ethoxides,potassium and sodium carbonates, and organic bases such as lower alkylamines such as ethylamine, diethylamine, triethyl-amine, tributylamine,and aromatic amines such as pyridine, the lutidines, and the like.

Treatment of the azasulfonium salt with the base results in rapidconversion of the azasulfonium salt through its unisolated intermediatesto the indole derivative having either formula VI or formula VIII if aβ-carbonyl sulfide reactant had been used, or to the formation ofintermediate having formula VII if the β-carbonyl sulfide acetal orketal had been used. The intermediate produce VII can be isolated, ifdesired, but this is not necessary. The crude reaction mixture can betreated with acid to form indole derivative of formula VI or VIIIdepending on the nature of R and R³.

As an example, a typical procedure could involve treating anilne inmethylene chloride solution at -65° C with tert-butyl hypochlorite, toform the N-chloroaniline, followed by the addition of methylthioacetaldehyde at -65° C, to form the azasulfonium salt and then withtriethylamine to obtain 3-methylthio indole in 30 percent yield. Similartreatment of 4-chloroaniline gives 3-methylthio-6-chloroindole in 35percent yield and 3-nitroaniline gives 3-methylthio-5-nitroindole in 38percent yields. These thio-ether products can be isolated and treatedwith Raney nickel to reduce thioethe indole derivatives; or with Raneynickel or an alkali metal aluminum hydride, or alkali metal borohydride,e.g., lithium aluminum hydride, sodium borohydride, or the like toreduce the methylthioindolenine compounds; or equivalent reducing agentsby known procedures to remove the 3-thiomethyl groups and to formindole, 6-chloroindole, and 5-aminoindole, respectively. In thereductions, the nitro substituent is also reduced to the amino group,which can be advantageous for some uses of the indole product.

Preferred reactants for use in this process are those wherein anN-chloroaniline of an N-chloroaminopyridine is reacted with a lowerα-alkylthio ketone or a lower α-alkylthio aldehyde, that is, thoseβ-carbonyl sulfides wherein R¹ is lower alkyl, R² is hydrogen loweralkyl or phenyl, and R³ is hydrogen or lower alkyl. When a ketal or anacetal of the β-carbonyl sulfide is used the preferred compounds arethose wherein R¹ is lower alkyl, R² is hydrogen lower alkyl or phenyl,R³ is hydrogen or lower alkyl and each R⁴ is lower alkyl or cyclic. R²can be bonded to R³ to form a ring, as indicated above.

Products produced by the process of this invention can be used for awide variety of purposes. The 3-thio-ether indoles can be used asintermediates to make the indoles without the thio-ether group. Indoleis known to be useful in perfumery in dilute concentrations. Thesecompounds can be used as perfume bases, as intermediates for makingplant hormones such as 3-indoleacetic acid, for making amino acids suchas tryptophane, for making indigoid and thioindigoid type compoundswhich are useful as vat dyes for fabrics, pigments for paints, printinginks, plastics, etc. In addition, compounds produced by the process ofthis invention can be used as intermediates to prepare serotonin,antiserotonin, and some antipsychotic agents, antihypersive drugs andthe like. See for example, A. Burger, Medicinal Chemistry, 3rd Edition,J. Wiley and Sons, New York, N.Y. (1970) pp. 70, 1038, 1413, 1451-1455,1458-59, 1484-85; J. Amer. Chem. Soc., 79, p. 3561 (1957); Experimentia,23, p. 298 (1967); Experientia, 16, 140 (1960); and M.S.L.D. Moustafa,Japan Journal of Tuberc., 9, 65 (1961) for references to products whichcan be prepared by known procedures from the indoles and indolederivatives from this invention. Also, produces of the process of thisinvention can be used to prepare the anti-inflammatory indomethacen andsimilar compounds disclosed in U.S. Pat. No. 3,161,654, as well asIndoxole, (an anti-inflammatory agent) indolmycin, an antibiotic, aswell as compounds disclosed in U.S. Pat. No. 3,686,213 which are usefulas diuretics, muscle relaxants, tranquilizers and inflammationinhibitors, for making antibacterial agents such as5,6-dibromo-3-(2-aminoethyl) indolenine derivative in TetrahedronLetters, (1973), page 299. The new compounds produced in the process ofthis invention are useful as intermediates in this process to prepareindoles and indole derivatives having the above exemplified uses.

The invention is further exemplified by the following detailed examplesand preparations which are given by illustration only. Temperaturesherein are in degrees centigrade unless otherwise indicated.

PREPARATION OF 3-METHYLTHIO-INDOLES

Methylthioacetaldehyde was obtained by refluxing 13 g. (0.095 mol) ofmethylthio-acetaldehyde dimethylacetal in 40 ml. of a 1 percent aqueoushydrochloric acid solution for 30 minutes. After cooling to roomtemperature, the solution was neutralized with saturated sodiumbicarbonate solution and extracted with methylene chloride. Themethylene chloride layer, after drying over anhydrous magnesium sulfate,filtering, and evaporating the solent, gave a residue which wasdistilled to yield 5.24 g. (0.05 mol, 62 percent) ofmethylthioacetaldehyde, b.p. 129°-134° ; n²⁵ D 1.4810.

Two general procedures for the synthesis of indoles were used.

METHOD A. -- SYNTHESIS OF INDOLES FROM ANILINES AND β-CARBONYL SULFIDES

To a vigorously stirred solution of about 0.044 mol of the aniline in150 ml. of methylene chloride at -65°, was added dropwise a solution of0.044 mol of tert-butyl hypochlorite in 20 ml. of the same solvent toform the N-chloroaniline. After 5 to 10 minutes, 0.044 mol of theβ-carbonyl sulfide (R³ = H) dissolved in 20 ml. of methylene chloridewas added causing an exotherm, and stirring at -65° C was continued for1 hour to insure complete reaction to form the azasulfonium chloridesalt. Usually the azasulfonium chloride salt had precipitated.Subsequently, 0.044 mol of triethylamine in 20 ml. of methylene chloridewas added to the azasulfonium salt mixture. After the addition wascompleted, the cooling bath was removed and the solution was allowed towarm to room temperature. Both rearragement and cyclization to form the2-substituted indole were complete at this point. A 50 ml. portion ofwater was added and the organic layer was separated, dried, filtered andevaporated. The residue was further purified by column chromatographyover silica gel using methylene chloride or a methylenechloride/chloroform mixture as the eluent.

Desulfurization of the 3-thio-ether indoles was accomplished by stirringa solution of 0.5 to 2.0 g. of the thioether indole in 50 ml. ofabsolute ethanol with an excess of W-2 Raney-nickel for 30 minutes.Filtration and evaporation gave a residue that was redissolved inmethylene chloride and dried. After filtration, the solvent was removedleaving the pure de-sulfurized indole in yields varying from 70 to 82percent.

W-2 Raney Nickel Preparation for Use

The W-2 Raney Nickel used in these experiments was obtained from W. R.Grace & Co., Raney Catalyst Division, South Pittsburg, Tennessee, as No.28 Raney Active Nickel Catalyst in Water. A portion of this was placedin a beaker and washed with distilled water until neutral to pH paperand then several more times with distilled water, three times with 95%ethanol, and three times with absolute ethanol. The catalyst underabsolute ethanol was stored in brown bottles until use.

METHOD B.-SYNTHESSIS OF INDOLES FROM ANILINES AND β-CARBONYL SULFIDEACETALS AND KETALS.

To a vigorously stirred solution of a 0.044 mol portion of the anilinein 150 ml. of methylene chloride at -65° there was added dropwise asolution of a 0.044 mol portion of tertbutylhypochlorite in 20 ml. ofthe same solvent to form the N-chloroaniline. After 5 to 10 minutes, a0.044 mol portion of the β-carbonyl sulfide acetal or ketal (R³ = H)dissolved in 20 ml. of methylene chloride was added causing an exotherm,and stirring at -65° C was continued for about 1 hour to insure completereaction to form the azasulfonium salt. Usually the azasulfonium salthad precipitated. Subsequently, a 0.044 mol portion of triethylamine in20 ml. of methylene chloride was added. After the base addition wascompleted, the cooling bath was removed and the solution was allowed towarm to room temperature. A 50 ml. portion of water was added and theorganic layer as separated, dried, filtered and evaporated, leaving anoily residue that mainly consisted of the unrearranged azasulfoniumsalt. To effect the rearrangement to intermediate compound VII theresidue was refluxed in 150 ml. of carbon tetrachloride containing 5 ml.of triethylamine overnight or until rearrangement was complete. When allof the azasulfonium salt was rearranged the solvent was removed and theresidue redissolved in 150 ml. of ethyl ether. Cyclization of the acetalor ketal intermediate to the indole ring system was effected by stirringthis solution for 3 hours with 50 ml. of 2 N hydrochloric acid. Afterseparation of the iquid layers, the ethereal layer was treated withsaturated sodium bicarbonate solution, dried, filtered and evaporated.The residue containing the 3-thio-ether indole product was recovered.Further purification can be effected by column chromatogrography oversilica gel using methylene chloride as the eluent.

Desulfurizaton of the 3-thio ether indole was accomplished in the mannerindicated above to form the indole compound.

EXAMPLE 1 - PREPARATION OF INDOLE A.α-Methylthio-α-(2-aminophenyl)-acetaldehyde dimethylacetal

The sub-titled compound was obtained from aniline andmethylthioacetaldehyde dimethyl acetal following procedure B as far asthe rearrangement. The product was purified by removal of the solvent togive an oily residue that was separated by column chromatography (silicagel-methylene chloride/ether 2:1) giving 5.70 g (0.025 mol, 57%) of thesub-titled compound. An analytical sample was obtained by distillation:bp 125°-128° (0.15 mm), n²⁵ D 1.5678; pmr (CCl₄) 2.82-3.67 (4H, aromaticprotons), 5.39 (1H, d, J=7 Hz), 6.02 (1H, d, J=7 Hz), 6.17 (2H, broad s,NH₂), 6.65 and 6.88 (3H, s, diastereometric OCH₃), and 8.22 (3H,s,SCH₃).

Anal. Calcd for C₁₁ H₁₇ NO₂ S: C, 58.12; H, 7.54; N, 6.16; S, 14.11.

Found: C, 58.01; H, 7.42; N, 6.15; S, 13.66.

B. Conversion of the dimethyl acetal from part A to 3-methylthioindolewas accomplished by stirring 0.50 g (2.20 mmol) of the dimethylacetaldissolved in 25 ml of ethyl ether for 2 hr. with 10 ml of 0.5 N aqueoushydrogen chloride. The ethereal layer was separated, treated with asaturated sodium bicarbonate solution, dried, filtered and evaporated toyield 0.35 g (2.14 mmol, 97%) of the oily 3-methylthioindole. This3-methylthioindole was treated with Raney nickel as described to formindole, identified by comparison with an authentic sample.

EXAMPLE 2 - PREPARATION OF 2-METHYLINDOLE A. 2-Methyl-3-methylthioindole

This compound was obtained from N-chloroaniline and methylthioacetonefollowing Method A, carried out on a 0.022 mol scale, which gave 2.68 g(0.015 mol, 69%) of the sub-titled product mp 58°-59° (recr. fromcyclohexane), bp 140°-142° (0.85 mm); ir 3400 cm⁻¹ (NH); pmr (CCl₄)2.25-3.20 (5H, m, aromatic H), 7.76 and 7.83 (s, 3, CH₃ and SCH₃).

Anal. Calcd for C₁₀ H₁₁ NS: C, 67.75; H, 6.26; H, 7.90.

Found: C,67.61; H,6.19; N, 7.87.

B. Desulfurization of the 2-methyl-3-methylthioindole (2.86 g, 0.022mol) gave in 79% yield 2-methylindole, identified by comparison with anauthentic sample.

EXAMPLE 3 -- PREPARATION OF 2,5-DIMETHYLINDOLE A.2.5-Dimethyl-3-methylthioindole

This compound was obtained from N-chloro-p-toluidine andmethylthio-acetone following Method A which gave 5.05 g (0.0265 mol,60%) of the sub-titled product: mp 110°-111° (recr. from cyclohexane);ir (KBr) 3350 cm⁻¹ (NH); pmr (CCl₄), 2.78 (1H, s, NH), 2.65 and 3.20 (1resp. 2H, s, aromatic H), 7.58, 7.79 and 7.86 (3H, s, CH₃).

Anal. Calcd for C₁₁ H₁₃ NS: C, 69.09; H, 6.85; N, 7.33; S, 16.73.

Found: C, 69.10; H, 6.86; N, 7.25; S, 16.73.

B. Desulfurization of 2,5-dimethyl-3-methylthioindole (0.50 g, 2.62mmol) with Raney nickel gave in 80% yield 2,5-dimethylindole asidentified by comparison with an authentic sample.

EXAMPLE 4 -- PREPARATION OF 5-ACETOXY-2-METHYLINDOLE A.5-Acetoxy-2-methyl-3-methylthioindole

This compound was obtained from N-chloro-4-acetoxyaniline andmethylthioacetone following Method A, carried ot on a 0.022 mol scale,which gave 3.55 g (0.015 mol, 68%) of the sub-titled product: mp129°-129.5°, (recr. from methanol); ir (KBr) 3340 (NH) and 1710 cm⁻¹(C═O); pmr (CCl₄), 1.90 (1H, s, NH) 2.92 and 3.48 (1 resp. 2H, s,aromatic H), 7.73, 7.78 and 7.94 (3H, s, CH₃).

Anal. Calcd for C₁₂ H₁₃ NO₂ S: C, 61.25; H, 5.57; N, 5.95; S, 13.63.

Found: C,60.91; H,5.61; N,5.90; S,13.57.

B. Desulfurizaton ofthe 5-acetoxy-2-methyl-3-methylthioindole (0.50g,2.13 mmol)(with Raney nickel) gave in 72% yield5-acetoxy-2-methyl-indole, mp 120°-132° (lit. 128°-130° ).

EXAMPLE 5 - PREPARATION OF 5-CHLORO-2-METHYLINDOLE A.5-Chloro-2-methyl-3-methylthioindole

This compound was prepared from N-chloro-4-chloroaniline andmethylthioacetone following Method A, which gave 6.68 g (0.032 mol, 72%)of the sub-titled product: mp. 64°-64.5° (recr. from cyclohexane ir(KBr) 3350 cm⁻¹ (NH); pmr (CCl₄), 2.42 (1H,s,NH), 2.52 and 3.15 (1 resp.2H,m,aromatic H), 7.72 and 7.90 (3H, s, CH₃ and SCH₃).

Anal. Calcd for C₁₀ H₁₀ ClNS: C,56.73; H,4.76; N,6.62; S,15.14

Found: C, 56.73; H,4.72; N,6.56; S,15.25. B. Desulfurization of5-chloro-2-methyl-3-methylthioindole (1.0 g, 4.73 mmol) gave in 74%yield 5-chloro-2-methylindole (mp 99°-100.5°, lit. 117°-119° ) asconfirmed by comparison of its ir spectrum with that of an authenticsample.

EXAMPLE 6 -- PREPARATION OF 4-NITRO-2-METHYL-3-METHYLTHIOINDOLE

A. 2-Methyl-3-methylthio-4-nitroindole

This compound was obtained from N-chloro-3-nitroaniline andmethylthioacetone following Method A with the modifications that (a)tetrahydrofuran (THF) was used as the solvent in view of the solubilityand (b) the mixture was stirred for 1 hr. after addition of thehypochlorite and 2 hr. after addition of the sulfide. In this way 8.07 g(0.036 mol, 82 %) of 4-nitro-2-methyl-3-methylthioindole was isolated:mp 148°-150° recr. from a CCl₄ /CHCl₃ mixture); ir (KBr) 3300 cm⁻¹ (NH);pmr (CDCl₃), 1.10 (1H, s, NH), 1.75-3.00 (3H, m, aromatic H), 7.40 and7.75 (3H, s, CH₃ and SCH₃).

Anal. Calcd for C₁₀ H₁₀ N₂ O₂ S: C, 54.04; H, 4.54; N, 12.60; S, 14.42.Found: C, 54.09; H, 4.58; N, 12.62; S, 14.49.

EXAMPLE 7 -- PREPARATION OF 2.7-DIMETHYLINDOLE A.2,7-Dimethyl-3-methylthioindole

This compound was obtained from N-chloro-2-methylaniline andmethylthioacetone following Method A, which gave 6.04 g (0.0316 mol,72%) of the sub-titled product: mp 59.5°-60.5° (recr. from cyclohexane);ir (KBr) 3360 cm⁻¹ (NH); pmr (CCl₄), 2.30-3.60 (4H, m, aromatic H),7.66, 7.74 and 7.85 (3H, s, CH₃, NCH₃ and SCH₃).

Anal. Calcd for C₁₁ H₁₃ NS: C,69.06; H, 6.85; N, 7.32 Found: C,69.05; H,6.85; N, 7.24.

B. Desulfurization of 2,7-dimethyl-3-methylthioindole (1.0 g, 5.23 mmol)gave in 73% 2,7-dimethylindole, mp 32°-33° (lit. 33°-35° ).

EXAMPLE 8 -- PREPARATION OF 1,2-DIMETHYLINDOLE A.1,2-Dimethyl-3-methylthioindole

This compound was obtained from N-chloro-N-methylaniline andmethylthioacetone following Method A. In this case, the organic layerwas extracted twice with 2N aqueous hydrochloric acid, after it had beenhydrolyzed with 50 ml of water. From the acid extracts 1.53 g (32.5%) ofN-methylaniline could be recovered. The organic layer gave in the usualwork-up procedure 3.02 g (0.016 mol, 36%, or 54% based on unrecoveredstarting aniline) of the sub-titled product: mp 59.5°-60° (recr. fromn-hexane); pmr (CCl₄), 2.45 and 2.96 (1 and 3H, m, aromatic H), 6.62(3H, s, NCH₃), 7.65 and 7.87 (3H, s, CH₃ and SCH₃).

Anal. Calcd for C₁₁ H₁₃ NS: C,69.06; H,6.85; N,7.32. Found: C,68.77;H,6.79; N,7.26.

B. Desulfurization of 1,2-dimethyl-3-methylthioindole (1.0 g, 5.23 mmol)gave in 76% yield 1,2-dimethylindole, mp 50°-52° (lit. 56° ).

EXAMPLE 9 -- PREPARATION OF 2-PHENYLINDOLE A.3-Methylthio-2-phenylindole

This compound was obtained from N-chloroaniline and methylphenacylsulfide following Method A, which gave 8.57 g (0.036 mol, 81%)of the sub-titled product: mp 106°-107° (recr. from 95% ethanol); ir(KBr) 3300 cm⁻¹ (NH); pmr (CCl₄), 2.00-3.00 (10H, m. aromatic H) and7.84 (3H, s, SCH₃).

Anal. Calcd for C₁₅ H₁₃ NS: C,75.28; H,5.48; N,5.85. Found: C,75.16;H,5.50; N,5.85.

B. Desulfurization of 3-methylthio-2-phenylindole (1.55 g, 6.50 mmol)gave in 74% yield 2-phenylindole, mp 186.5°-187.5° (lit. 186° ), whichir spectrum was identical to that of an authentic sample.

EXAMPLE 10 -- PREPARATION OF INDOLE A. 3-Methylthioindole

The compound was obtained from N-chloroaniline andmethylthioacetaldehyde following Method A which gave 1.06 g (6.5 mmol,30%) of the sub-titled product: bp 112.5°-113° (0.15 mm), n²⁵ D 1.6488;ir 3340 cm⁻¹ (NH); pmr (CCl₄), 2.40 and 3.05 (2 resp. 4H, m, aromatic H)and 7.82 (3H, s, SCH₃).

Anal. Calcd for C₉ H₉ NS: C,66.22; H,5.56; N,8.58. Found: C,66.11;H,5.57; N,8.52.

B. Desulfurization of 3-methylthioindole (1.7 g, 0.01 mol) gave indolein 82% yield, as confirmed by comparison with an authentic sample.

EXAMPLE 11 -- PREPARATION OF 5-CHLOROINDOLE A.5-Chloro-3-methylthioindole

This compound was obtained from N,4-dichloroaniline andmethylthioacetaldehyde following Method A, but using tetrahydrofuran asthe solvent. On column chromatography 1.72 g of the starting anilinecould be recovered and 3.00 g (0.0152 mol, 35%, or 50% calculated onunrecovered aniline) of the subtitled product was isolated: bp134.5-135.5 (0.20 mm); ir 3370 cm⁻¹ (NH); pmr (CCl₄), 1.90 (1H, s, NH),2.37 (1H, s, aromatic H), 2.93 (3H, m, aromatic H) and 7.72 (3H, s,SCH₃).

Anal. Calcd for C₉ H₈ ClNS: C, 54.68; H, 4.08; N, 7.09; S, 16.22. Found:C,54.44; H,4.13; N,7.13; S, 16.02.

B. Desulfurization of 5-chloro-3-methylthioindole with Raney nickelgives 5-chloroindole.

EXAMPLE 12 -- PREPARATION OF 3-METHYLTHIO-4-NITROINDOLE A.3-Methylthio-4-nitroindole

This compound was obtained from N-chloro-3-nitroaniline andmethylthioacetaldehyde following Method A, with the modification thattetrahydrofuran was used as the solvent. In addition, the mixture wasstirred for 1 hr after addition of the hypochlorite. After hydrolysiswith water, the reaction mixture was extracted with 1N aqueoushydrochloric acid to remove any remaining nitroaniline. In this way 3.50g (0.017 mol, 38%) of 3-methylthio-4-nitroindole was obtained as a blackcrystalline material: mp 123°-124° (recr. from ethanol); ir (KBr) 3310cm⁻¹ (NH); pmr (CDCl₃), 1.03 (1H, s, NH), 2.20-3.00 (4H, m, aromatic H),and 7.63 (3H, s, SCH₃).

Anal. Calcd for C₉ H₈ N₂ O₂ S: C,51.91; H,3.87; N,13.45; S,15.37. Found:C, 51.79; H,3.86. N,13.37. S,15.41.

B. Desulfurization of 3-methylthio-4-nitroindole with Raney nickel gives4-aminoindole.

EXAMPLE 13 -- PREPARATION OF 5-CHLOROINDOLE A.5-Chloro-3-methylthioindole

This compound was obtained from 4-dichloroaniline andmethylthioacetaldehyde dimethyl acetal by Method B giving 2.00 g (0.0102mol, 23%) of product identical to that in Example 11 A.

B. Desulfurization with Raney nickel as described above gives5-chloroindole.

EXAMPLE 14 -- PREPARATION OF 5-METHYLINDOLE A.5-Methyl-3-methylthioindole

This compound was obtained from N-chloro-4-methylaniline andmethylthioacetaldehyde dimethyl acetal by Method B which gave 2.75 g(0.017 mol, 39%) this intermediate product, bp 125°-126° (0.20 mm), n²⁵D 1.6332; ir 3340 cm⁻¹ (NH); pmr (CCl₄), 2.45 (1H, s, NH), 2.55 (1H, s,aromatic H), 3.06 (3H, m, aromatic H), 7.57 and 7.75 (3H, s, CH₃ andSCH₃).

Anal. Calcd C₁₀ H₁₁ NS: C,67.75; H,6.26; N,7.90. Found: C, 67.52;H,6.29; N,7.90.

B. Desulfurization of 5-methyl-3-methylthioindole (1.0 g, 5.65 mmol)gave an 82% yield of 5-methylindole, mp 55°-56.5° (lit. 58.5).

EXAMPLE 15 -- PREPARATION OF 3-METHYLTHIO-4-NITROINDOLE A.3-Methylthio-4-nitroindole

This compound was obtained from N-chloro-3-nitroaniline andmethylthioacetaldehyde dimethyl acetal following Method B giving 0.75 g(3.6 mmol, 38%) of the 3-Methylthio-4-nitroindole.

B. Desulfurization with Raney nickel as described above gives4-aminoindole.

EXAMPLE 16 -- PREPARATION OF 2-METHYL-5-NITROINDOLE A.2-Methyl-3-methylthio-5-nitroindole

To a suitable reaction vessel there was added 6.07 g (0.044 mol) of4-nitroaniline dissolved in 300 ml of methylene chloride. The solutionwas cooled with vigorous stirring to -65°, giving a suspension of thenitro compound. A solution of 5.75 g (0.055 mol) of t-butyl hypochloritein 10 ml of methylene chloride was added to form the4-nitro-N-chloroaniline and subsequently after 3 hr, 7.4 g (0.071 mol)of methylthio-2-propanone in 10 ml of methylene chloride was added,while stirring was continued for 10 hr. to form the azasulfoniumchloride salt. The triethylamine, 4.4 g (0.044 mol), dissolved in 10 mlof methylene chloride was added and the solution was warmed to roomtemperature to form the 2-methyl-3-methylthio-5-nitroindole. A 50-mlportion of water was added and after separation, the organic layer wasextracted thoroughly with a 2N aqueous hydrochloric acid. Drying overanhydrous magnesium sulfate and filtration of the organic solution wasfollowed by evaporation, leaving a solid residue that was stirred forseveral hr with 30 ml of benzene. The remaining precipitate wascollected by filtration giving 2.92 g (0.013 mol, 30%) of2-methyl-3-methylthio-5-nitroindole, mp 197.5°-198.5° (recr. from 95%ethanol); ir (KBr) 3250 cm⁻¹ (NH); pmr (acetone-d₆) 1.40 (1H, br, s,NH), 1.02 (1H, d, J═2.0Hz,4-aryl H), 2.02 (1H, dd, J═8.0 and 2.0 Hz,6-aryl H), 2.57 (1H, d J═9.0 Hz, 7-aryl H) and 7.42 and 7.73 (3H, s,SCH₃ and CH₃).

Anal. Calcd for C₁₀ H₁₀ N₂ O₂ S: C, 53.84; H,4.58; N,12.55; S,14.48.Found: C,54.05; H,4.54; N,12.50; S,14.42. Found C,54.05; H,4.54;N,12.50; S,14.42.

B. De-methylthiolation with Raney nickel gives the2-methyl-5-aminoindole.

EXAMPLE 17 -- PREPARATION OF 5-CARBOETHOXY-2-METHYLINDOLE

A. Following general procedure A above5-carboethoxy-2-methyl-3-methylthioindole was prepared from theN-chloro-derivative of benzocaine and methylthio-2-propanone, with themodification that the suspension of benzocaine in 150 ml of methylenechloride was stirred for 30 minutes at -65° with the tert-butylhypochlorite solution before addition of the sulfide. After addition ofthe methylthio-2-propanone, 100 ml of methylene chloride was added topromote stirring. Stirring was continued for 6 hours to insure completereaction before addition of the base. The oily residue, obtained afterwork-up of the reaction mixture, was purified by stirring with 50 ml ofethyl ether, giving, upon filtration, 6.37 g (0.026 mol, 58% yield) of5-carboethoxy-2-methyl-3-methylthioindole, m.p. 126°-127° C.(recrystallized from absolute ethanol); ir (KBr) 3250 (NH) and 1650 cm⁻¹(C═O); pmr (CDCl₃) 0.84 (1H,s,NH), 1.35 (1H, d, J═1.5 Hz, 4-aryl H),2.16 (1H, dd, J═8.0 and 1.5 Hz, 5-aryl H), 2.89 (1H, d J═8.0 Hz, 7-arylH), 5.61 (2H, q, J═7.0 Hz, OCH₂), 7.52 and 7.80 (3H, s, CH₃ and SCH₃)and 8.59 (3H, t, J═7.0 Hz, OCH₂ CH₃).

Anal. Calcd for C₁₃ H₁₅ NO₂ S: C, 62.63; H, 6.06; N, 5.62; S, 12.86.Found: C, 62.54; H, 6.19; N, 5.63; S, 12.79.

B. 5-Carboethoxy-2-methylindole was obtained by desulfurization of5-carboethoxy-2-methyl-3-methylthioindole, (1.0 g, 4.02 mmol), by thede-methylthiolation with Raney nickel giving 0.68 g (3.35 mmol, 83%) of5-carboethoxy-2-methylindole, mp 140°-141° C. (recr. from benzene); ir(KBr) 3250 (NH) and 1650 cm⁻¹ (C═0); pmr (CDCl₃) 1.66 (2H, br, s, NH and4-aryl H), 2.13 (1H, dd J═8.0 and 1.5 Hz, 6-aryl H), 2.83 (1H, d, J═8.0Hz, 7-aryl H), 3.68 (1H, s, 3-aryl H), 5.60 (2H, q, J═7.0 Hz, OCH₂),7.56 (3H, s, CH₃) and 8.58 (3H, t, J═7.0 Hz, OCH₂ CH₃).

Anal. Calcd for C₁₂ H₁₃ NO₂ : C,70.92; H,6.45; N,6.89 Found: C,71.07;H,6.43; N,6.87.

EXAMPLE 18 -- PREPARATION OF 5-CARBETHOXYINDOLE

A. Following the general procedure A, 5-carboethoxy-3-methylthioindolewas prepared by converting benzocaine to N-chlorobenzocaine, andreacting the N-chlorobenzocaine with methylthioacetaldehyde to form theazasulfonium salt therefrom, followed by treating the azasulfonium saltreaction mixture with triethylamine to form the5-carboethoxy-3-methylthioindole.

In the work-up of the reaction mixture 50 ml of water was added afterwarming to room temperature, the layers were separated and the organicsolution was concentrated. The residue was redissolved in 100 ml ofethyl ether, extracted with 2N aqueous hydrochloric acid to removeunreacted benzocaine, treated with sodium bicarbonate solution, driedover anhydrous magnesium sulfate, filtered and evaporated, leaving aresidue that was subjected to column chromatography (silica gel). Therewas obtained 2.58 g (0.011 mol, 25%) of 5-carboethoxy-3-methylthioindolemp, 89.0°-90.5° (recr. from CCl₄); ir (KBr) 3220 (NH) and 1650 cm⁻¹(C═O); pmr (CCl₄) 0.69 (1H, s, NH), 1.52 (1H, d, J═1.5 Hz, 4-aryl H),2.10 (1H, dd J═8.0 and 1.5 Hz, 6-aryl H), 2.70 (2H, m, 2- and 7-aryl H),5.56 (2H, q, J═7.0 Hz, OCH₂), 7.67 (3H, s, SCH₃), 8.54 (3H, t J═7.0 Hz,OCH₂ CH₃).

Anal. Calcd for C₁₂ H₁₃ NO₂ S: N,5.95; S,13.63. Found: N,5.74; S,13.32.

5-Carbethoxyindole was obtained by desulfurization of5-carboethoxy-3-methylthioindole, (0.53 g, 2.25 mmol) in the mannerdescribed above giving 0.31 g (1.64 mmol, 73%) of 5-carboethoxyindole mp94°-95° (recr. from cyclohexane); ir (KBr) 3320 (NH) and 1660 cm⁻¹(C═O); pmr (CCl₄) 0.68 (1H, s, NH), 1.60 (1H, br, s, 4-aryl H), 2.14(1H, dd J═8.0 and 1.5 Hz, 6-aryl H), 2.70 (2H, m, aryl H), 3.48 (1H, m,aryl H), 5.62 (2H, q J═ 7.0 Hz, OCH₂) and 8.61 (3H, t, J═7.0 Hz, OCH₂CH₃).

Anal. Calcd for C₁₁ H₁₁ NO₂ : C, 69.83; H,5.86; N,7.40. Found: C,69.68;H,5.81; N,7.34.

EXAMPLE 19 -- PREPARATION OF A MIXTURE OF 2,4-DIMETHYL-AND2,6-DIMETHYL-INDOLES

A. Following the general procedure of A, m-toluidine was converted tothe N-chloro-m-toluidine. The N-chloro-m-toluidine was reacted withmethylthio-2-propanone to form the azasulfonium chloride salt. Theazasulfonium chloride salt was reacted with triethylamine to form themixture of the 2,4-dimethyl- and 2,6-dimethyl-3-methylthioindoles. Aftercolumn chromatography (silica gel-methylene chloride) there was isolated4.87 g (0.026 mol, 58%) of the substantially pure isomeric mixture(resp. ratio 41:59) as an oil: ir 3400 cm⁻¹ (NH); pmr, (CCl₄) 2.50-3.60(4H, m, aryl H), 7.20 (s, 4, --CH₃), 7.65 (s,6,--CH₃), 7.08, 7.93 and7.96 (s, SCH₃ and 2-CH₃), all these singlets together account for anintergration of 9H.

B. Desulfurization of this mixture (2.52 g, 13.2 mmol) was accomplishedby Raney nickel reduction procedures giving 1.19 g (8.25 mmol, 62.5%) ofa mixture of 2,4-dimethyl- and 2,6-dimethylindole as a solid in arespective ratio of 34:66 pmr (CCl₄) 2.60-4.20 (5H, m, aryl H), 7.17,7.62, 7.94 and 8.00 (s, CH₃ and SCH₃ ; total intergration for 6H).

Both mixtures could not be preparatively separated by availablelaboratory techniques.

EXAMPLE 20 -- PREPARATION OF 3-METHYLTHIO-7-AZAINDOLE AND 7-AZAINDOLE

To a stirred solution of 2-aminopyridine (4.70 g, 0.05 mole) in 100 mlof methylene chloride at -65° was added dropwise a solution of a t-butylhypochlorite (5.43 g, 0.05 mole) in 20 ml of methylene chloride cooledin a Dry-Ice/acetone bath to form the N-chloro-2-aminopyridine. Thereaction mixture was stirred for 1 hr. Thiomethylacetaldehyde dimethylacetal¹ (6.80 g, 0.05 mole) in 10 ml of methylene chloride cooled in aDry-Ice acetone bath was introduced and stirred for 1.5 hr to form theazasulfonium salt. Sodium methoxide (3.0 g, 0.055 mole) in 50 ml ofabsolute methanol cooled in a Dry-Ice/acetone bath was added and thereaction mixture was stirred for 2.5 hr. Work-up of the reaction mixtureby the standard procedure gave an intermediate which was mixed withpotassium t-butoxide (5.6 g, 0.05 mole) in 300 ml of t-butyl alcohol.The mixture was refluxed for 5.5 hr. Rearrangement to the desiredsulfide was shown to be complete by thin layer chromatography. Water wasadded to the reaction mixture when it was cooled to room temperature andthe reaction mixture was extracted with diethyl ether. The combinedethereal extracts were concentrated on the rotary evaporator to give anoil which was taken up in 100 ml of 0.1 N aqueous hydrochloric acid and100 ml of diethyl ether and stirred for 4.5 hr at room temperature. Theaqueous layer was separated, basified with a saturated aqueous solutionof sodium bicarbonate, and extracted with diethyl ether. The etherealwere combined, dried, and concentrated to give crude3-methylthio-7-azaindole (6.0 g) which was chromatographed on silica gel(Skelly Solve B and ethyl ether) to give white crystalline titledproduct (3.70 g, 45%), m.p. 115.0°-115.5°; nmr (CDCl₃) 2.36 (s,3H), 7.35(d of d, 1H), 7.50 (s, 1H), 8.10 (d of d, 1H), 8.40 (d of d, 1H), and12.72 (broad s, 1H).

Exact Mass Molecular Weight. Calcd for C₈ H₈ N₂ S: 164.0408. Found:164.0410 Anal. Calcd for C₈ H₈ N₂ S: C,58.51; H,4.91; N,17.06; S,19.52.Found: C,58.47; H,5.20; N,17.12; S,19.51.

De-methylthiolation with Raney nickel gives 7-azaindole.

EXAMPLE 21 -- PREPARATION OF TETRAHYDROCARBAZOLE

A. 11-Methylthio-1,2,3,4-tetrahydrocarbazolenine was obtained by addingdropwise to a vigorously stirred solution of 0.044 mol of aniline in 150ml of methylene chloride cooled to -65° a solution of 0.044 mol oft-butylhypochlorite in 20 ml of the same solvent. After a 5 min. period0.044 mol of 2-methylthiocyclohexanone in 20 ml of methylene chloridewas added causing a slight exotherm and stirring was continued for 1 hr.The intermediate azasulfonium salt did not precipitate. Subsequently,0.044 mol of triethylamine in 20 ml of methylene chloride was added andafter the addition was completed the cooling bath was removed to allowthe solution to warm to room temperature. A 50-ml portion of water wasadded and the organic layer was separated, dried over anhydrousmagnesium sulfate, filtered and evaporated. The residue was subjected tocolumn chromatography (SiO₂ -methylene chloride), giving 5.58 g (0.0257mol, 58%) of 11-methylthio-1,2,3,4-tetrahydrocarbazolenine as an oilthat solidified on standing in the refrigerator: mp 48°-50° (recr. fromn-hexane), bp 87°-88° (0.05 mm); ir 1690 cm⁻¹ (N═C); pmr(CCl₄)τ2.50-3.20 (4H, m, aryl-H), 7.00-8.95 (8H, m, aliphatic H), 8.84(3H, s, SCH₃). Anal. Calcd for C₁₃ H₁₅ NS: N,6.45. Found: N, 6.40.

B. 1. Conversion of 11-Methylthio-1,2,3,4-tetrahydrocarbazolenine to1,2,3,4-tetrahydrocarbazole.

This conversion was achieved by adding to an ice-cooled solution of 634mg (2.92 mmol) of the thio-ether indolenine in 20 ml of anhydrous ether,portion wise 159 mg (4.18 mmol) of lithium aluminum hydride. The mixturewas stirred for 40 min. at room temperature and then hydrolyzed with 30ml of 0.5N aqueous sulfuric acid. The layers were separated and theaqueous phase was extracted twice with 30-ml portions of ether. Thecombined organic solutions were treated with saturated sodiumbicarbonate solution, dried over anhydrous magnesium sulfate, filteredand evaporated, leaving 520 mg (mp. 110°-116.5° ) of a residue that waspurified further by column chromatography (SiO₂ -methylene chloride). Inthis way 400 mg (2.34 mmol, 80%) of 1,2,3,4-tetrahydrocarbazole, mp114.5°-117° (lit. mp. 116° ), was obtained.

B. 2. Conversion of 11-Methylthio-1,2,3,4-tetrahydrocarbazolenine to1,2,3,4-tetrahydrocarbazole.

This was achieved by refluxing a mixture of 687 mg (3.17 mmol) of thethio-ether indolenine and 363 mg (9.81 mmol) of sodium borohydride in 20ml of isopropanol for 16 hr. A 20-ml portion of water was added and themixture was extracted twice with 30-ml portions of methylene chloride.The organic extracts were dried over anhydrous magnesium sulfate,filtered, and evaporated, leaving 500 mg (mp 105°-111° ) of a residue,that was purified further over a column (SiO₂ -methylene chloride). Inthis manner 438 mg (2.02 mmol, 64%) of 1,2,3,4-tetrahydrocarbazole, mp.111°-114° was obtained.

B. 3. Conversion of 11-Methylthio-1,2,3,4-tetrahydrocarbazolenine to1,2,3,4-tetrahydrocarbazole.

This was achieved by stirring 798 mg (3.67mmol) of the thio-etherindolenine in 30 ml of absolute ethanol for 30 min with 2 spoons ofRa-Ni W-2. Workup as for the formerly described desulfurizations gave521 mg (3.05 mmol, 83%) of 1,2,3,4-tetrahydrocarbazole, mp. 115°-117.5°.

Additional compounds which can be prepared by the procedures describedabove include:

5-cyanoindole from N-chloro-4-cyanoaniline and methylthioacetaldehyde;

6-(N,N-diethylamino)indole from N-chloro-3-(N,N-diethylamino) anilineand methylthioacetaldehyde;

4,5-dichloroindole from N,3,4-trichloroaniline andmethyltrioacetaldehyde;

6-propionoxy-2-methylindole from N-chloro-3-propionoxyaniline andmethylthioacetone;

5-butoxycarbonylindole from N-chloro-4-butoxycarbonylaniline andmethylthioacetaldehyde;

6-phenoxycarbonylindole from N-chloro-3-phenoxycarbonylaniline andmethylthioacetaldehyde;

N,5-dimethylindole from N-chloro-N-methyl-4-methylaniline andmethylthioacetaldehyde;

N-benzyl-5-nitroindole from N-chloro-N-benzyl-4-nitroaniline andmethylthioacetaldehyde;

N-phenyl-5-cyanoindole from N-chloro-N-phenyl-4-cyanoaniline andmethylthioacetaldehyde;

N-propyl-2-methylindole from N-chloro-N-propylaniline andmethylthioacetone;

5-azaindole from 4-(N-chloroamino) pyridine and methylthioacetaldehyde;

4-aza-7-chloroindole from 3-(N-chloroamino)6-chloropyridine andmethylthioacetaldehyde;

5-chloro-3-methylindole from N,4-dichloroaniline and2-(methylthio)-propionaldehyde;

2,3-dimethylindole from N-chloroaniline and 3-methylthio-2-butanone;

6-methyltetrahydrocarbazole from N-chloro-p-toluidine and3-methylthio-2-butanone;

6-aza-2-benzylindole from 4-(N-chloroamino) pyridine and1-methylthio-3-phenyl acetone, and the like.

The acetal or ketal forms of the β-carbonyl sulfide reactants can beused to prepare the compounds by the Method B procedure.

I claim:
 1. A compound of the formula: ##STR10##wherein X is --CH═ or--N═; each of Y and Z is hydrogen, fluorine, chlorine, bromine, iodine,nitro, cyano, N,N-di-lower alkylamino, lower alkyl, lower alkyloxy,lower acyloxy, carbonyloxy-lower alkyl or carbonyloxyphenyl and, exceptwhen both y and Z are hydrogen, not more than one of Y and Z is ortho tothe amine nitrogen, R is hydrogen or a hydrocarbon radical free ofaliphatic unsaturation and containing from 1 to 8 carbon atoms, R¹ islower alkyl, phenyl, or benzyl, R² is hydrogen, lower alkyl, or phenyl,R³ is hydrogen, lower alkyl, phenyl, or benzyl, or R² and R³ are takentogether with the carbons to which they are bonded to complete a ringcontaining 5 to 8 carbon atoms, and A is chlorine or bromine.
 2. Acompound of the formula: ##STR11##wherein X, Y, Z, R, R¹, R², R³ and Aare as defined in claim 1 and each R⁴ is lower alkyl, or the two R⁴radicals are taken together with the ##STR12##moiety to which they arebonded to complete a ring containing from 3 to 4 carbon atoms.